Over the past several decades, the worldwide incidence of skin cancer has been increasing at an alarming rate. The reason for the dramatic increase in skin cancers that has occurred over this period and the human suffering associated with these diseases is not entirely clear. Many experts believe that it is due, at least in part, to depletion of the earth's protective ozone layer. The widespread use of sunscreens that protect against some but not all of the sun's harmful UV radiation (UVB but not UVA) has also played a role. According to the National Cancer Institute (NCI), there will be over one million new cases of skin cancer reported in the United States in the year 2001 and approximately 7000 deaths. This nears the total of all other cancers combined. NCI also reports that if present trends continue 40–50% of fair skinned Americans now living are expected to develop at least one type of skin cancer by age sixty-five. These numbers are alarming, but in regions of the world closer to the equator, the rates of skin cancer are even higher.
In some regions of Australia for example, the probability of non-indigenous people (most of whom are of European descent) developing skin cancer at some point during their lifetime approaches 100%. Skin cancers are now the main cause of death in Australia of all persons between the ages of 25 and 40. Worldwide, skin cancer is expected to become the leading cause of death due to malignant disease in the next decade.
How did this alarming situation come about? The worldwide pandemic of skin cancers is probably not due to a single cause but more likely is due to a number of causal factors. These include lifestyle choices (suntanning, increased outdoor leisure activities), an aging population (accumulated skin damage due to chronic sun exposure and decreased DNA repair capacity with age) dietary factors (folic acid is the most common nutritional deficiency in the world and other micro-nutrient deficiencies) and environmental factors (workplace hazards and depletion of the ozone layer). In addition to increased risk of skin cancer, exposure to sunlight has a variety of adverse effects on the human body, including erythema (burning of the skin), photoaging (wrinkling) and suppression of the immune system. Recently, it has also been suggested that sunlight exposure in women might also increase the risk of neural tube defects in the developing fetus and risk of developing endometriosis (a condition characterized by invasion of the inner lining (endometrium) tissue into the outer layers of the uterus.)
Many of the effects of solar light on the human body are interrelated. For example, children who experience only a single episode of blistering sunburn in childhood (before the age of 18) double their risk of developing skin cancer later in life. Tanning of the skin was long thought to be an important component of a healthy lifestyle. It is now considered by most experts to be quite the opposite and should be more properly considered as the unhealthy appearance of sundamaged skin. In addition, contrary to another widely held belief, it is now well documented that tanning confers no protection whatsoever against the most serious effect of chronic sun exposure, the increased risk of skin cancer.
The skin cancers induced by sunlight can be broadly categorized into two types: melanomas and non-melanomas (basal cell and squamous). It was generally accepted for some time that exposure to UVB (the burning rays of the sun with the wavelengths ranging from 280 to 315 nm) was responsible for the induction of melanomas, the most serious form of skin cancer and the tumor type responsible for most deaths. This was held to be especially true in those individuals who had at least one episode of severe sunburn early in childhood. It seems likely from more recent studies, (especially an elegant series of experiments by Dr Richard Setlow reported recently to the annual meeting of the American Academy of Dermatology) that this is simply not the case. Based on spectral and mutational fingerprint analysis (each type of UV light causes a characteristic mutational pattern in target genes) Dr Setlow has suggested that melanomas are due mainly to chronic exposure to UVA. Wrongly considered by many people to be the harmless tanning rays of the sun, UVA has wavelengths between 320 and 400 nm. UVA has less energy than UVB but is more penetrating and passes through window glass and into deeper layers of the skin more easily.
There are several implications of this more detailed understanding of the carcinogenic potential of UVA and UVB. First, UVA light passes easily through the atmosphere and is not absorbed by the ozone layer. It is the main type of solar UV irradiation (about 95%) that reaches the surface of the earth. In the past, it was generally believed that UVA had only beneficial effects to humans such as stimulation of vitamin D formation and tanning. However, this is clearly not the case. Wavelengths in the UVA range are damaging to the skin, cause photoaging and are causally related to the induction of melanomas.
Second, depletion of the ozone layer and the concomitant increase in the amount of UVB light reaching the surface of the earth cannot be the explanation for the dramatic increase in melanomas seen worldwide in recent years. More likely it is due to the widespread use of sunscreen products that slow burning of the skin by filtering UVB and giving a false impression to the user that sun damage is not occurring. These individuals are not only at greater risk of melanoma formation but also increased risk of photoaging of the skin and suppression of their immune system.
Last, chronic exposure to UVA over the lifetime of an individual and not acute sunburn in childhood is now considered to be the main causative factor in the induction of melanomas, the most serious form of skin cancer and the type causing most deaths (six out of seven deaths due to skin cancer in the United States are caused by melanomas). The general implication of these findings is that tanning is unhealthy whether done in sunlight or by exposure to artificial sources of UVA such as those used in salons. The US FDA now recommends that people avoid tanning salons altogether and that sunscreen products should contain both UVA and UVB filters.
The mechanism of UV damage to skin is only partly understood. The harmful effects of UVA and UVB light on human skin are due primarily to direct cellular damage (see Principles and Practice of Dermatology, 2nd Edition, Williams and Wilkins, Churchill/Livingston, N.Y.). Suppression of the immune system also occurs but by an indirect mechanism. The genotoxic potential of solar light resides mainly in the ability of UV to damage DNA (DNA absorbs maximally at 254 nm). UV light causes the formation of various photoproducts in the strands of the DNA molecule. The major photoproducts caused by UV light are dimers (fusions) of adjacent pyrimidines (thymine or cytosine residues) in one of the two strands of the DNA molecule. Other minor products like 6,4 photoproducts also occur. DNA is not the only target of UV light. UV also damages other cellular components such as collagen and causes photoaging of the skin. But the main genotoxic (mutagenic and carcinogenic) effects of UV light seem to reside in the ability of UV wavelengths to damage DNA. The cancer causing effects of UV light are can also reside in the ability of these wavelengths to impair the body's immunosurveillance system whose job it is to detect and destroy potentially malignant cells. In the absence of a properly functioning immunosurveillance system, cells harboring tumorigenic mutations caused by sunlight are more likely to proceed to malignancy. In the art, numerous screening and filtering agents have been developed over many years, to protect skin against the deleterious affects of UV light. These agents are applied directly to the skin of a subject, and are believed to prevent UV light from penetrating the epidermis by acting as “filters,” thereby absorbing or otherwise dissipating the energy contained in photons of UV light. Previously it was widely accepted in the industry that agents called “sunblocks” decreased UV-induced DNA damage, and in particular, pyrimidine dimer formation by UV opaque substances. In support of this view a recent clinical study indicated that “sunblocks” such as titanium oxide significantly reduced the incidence of pre-cancerous skin lesions in sunlight-exposed subjects.
However, the Food and Drug Agency (FDA) no longer accept the term “sunblock”. The FDA believes the term is misleading as no agent truly “blocks” all harmful UV rays and the term should be disallowed as it implies a greater degree of protection from the damaging effects of sunlight than is warranted.
Para-aminobenzoic acid (pABA) was one of the first sunfiltering agents to be identified in the art. It is now seldom used because of problems with contact dermatitis. Due to widespread use of PABA over many years about 10% of all users of sunscreen products have some degree of contact sensitivity to the compound. However, esters of PABA, particularly octyl, dimethyl, para-aminobenzoic acid, do not elicit these same skin reactions. Other commonly used sunfilters are compounds from the salicyclate, cinnamate, benzophenone, anthranilate, and dibenzoylmethane families of molecules. It is well known in the art to combine sunfiltering agents that absorb UV light in different portions of the spectrum. However, most of these agents are synthetic chemicals not found in commonly in nature and it is not known what effects long-term use of these compounds may have on the human body.
Sunscreen compositions exert their effects through filtering or absorbing UV light so that the damaging wavelengths do not penetrate the various layers of the skin. To be effective, sunscreens must be present on the skin as a continuous film, and must remain on the surface of the skin throughout the period of UV exposure. One of the problems with products currently in use is that despite numerous attempts to develop topical compositions that act as sunscreen carriers and remain on the surface of the skin (see U.S. Pat. No. 5,087,445), sunscreens tend to rub off on towels and clothing, and wash off in perspiration, or during swimming, showering and bathing. Even if carriers are developed that remain on the surface of the skin for longer periods absorption of sunscreen (and cosmetic) additives into the skin remains a problem. This is due to the surprising fact that many sunfiltering agents used as sunscreen and cosmetic additives themselves cause DNA damage. Titanium dioxide for example a very common additive has long been considered to be safe and effective as a sunscreening agent. This may not be the case (see Salinaro et al., 1997, “Chemical oxidation and DNA damage catalyzed by inorganic sunscreen ingredients” FEBS Lett 418:87–90). Padimate-O, another common sunscreen additive in widespread use may also be genotoxic (see P. J. McHugh and J. Knowland, 1997, “Characterization of DNA damage inflicted by free radicals from a mutagenic sunscreen ingredient and its location using an in vitro genetic reversion assay” Photochem Photbiol 66:276–281.]
A recent research article (G. J. Cameron et al., 1997, “Systemic absorption of sunscreen after topical application” The Lancet 350: 863–864) has shown that the UVA sunscreen oxybenzone, a benzophenone derivative used commonly worldwide to make sunscreen products with high sun protection factors (SPF) is absorbed systemically and excreted in human urine soon after application to the skin. The repeated use of a sunscreen that is absorbed systemically could pose an especially high risk to human health if the sunscreen agent is chronically genotoxic. Taken as a whole, these data suggest that many of the sunscreen agents currently in widespread human use are carcinogenic. This has added a new urgency to the development of novel non-genotoxic sunfiltering agents. These agents should not only be effective in reducing the harmful effects of UV light, but also should be safe for human use, even upon repeated usage and over a long period of time. The present invention is submitted in an attempt to address this need.